Analyzing the worldwide progression of COVID-19 cases and deaths using nonlinear mixed-effects model.

COVID-19 is an infectious disease that continues to spread worldwide. A precise estimation of the cases and deaths due to COVID-19 would allow for appropriate consideration of healthcare resource allocation, public health response, and vaccination and economic planning, to minimize social damage. In this study, we analyzed the progression of COVID-19 cases and deaths until January 2022 in 156 countries using a nonlinear mixed-effect model based on the SIR framework.

Disease progression modeling with temporal realignment: An emerging approach to deepen knowledge on chronic diseases.

The recent development of the first disease-modifying drug for Alzheimer's disease represents a major advancement in dementia treatment. Behind this breakthrough is a quarter century of research efforts to understand the disease not by a particular symptom at a given moment, but by long-term sequential changes in multiple biomarkers. Disease progression modeling with temporal realignment (DPM-TR) is an emerging computational approach proposed with this biomarker-based disease concept.

Predicting the in vivo developmental toxicity of fenarimol from in vitro toxicity data using PBTK modelling-facilitated reverse dosimetry approach.

In vitro methods are widely used in modern toxicological testing; however, the data cannot be directly employed for risk assessment. In vivo toxicity of chemicals can be predicted from in vitro data using physiologically based toxicokinetic (PBTK) modelling-facilitated reverse dosimetry (PBTK-RD). In this study, a minimal-PBTK model was constructed to predict the in-vivo kinetic profile of fenarimol (FNL) in rats and humans.

Data-driven disease progression model of Parkinson's disease and effect of sex and genetic variants.

As Parkinson's disease (PD) progresses, there are multiple biomarker changes, and sex and genetic variants may influence the rate of progression. Data-driven, long-term disease progression model analysis may provide precise knowledge of the relationships between these risk factors and progression and would allow for the selection of appropriate diagnosis and treatment according to disease progression. To construct a long-term disease progression model of PD based on multiple biomarkers and evaluate the effects of sex and leucine-rich repeat kinase 2 (LRRK2) mutations, a technique derived from the nonlinear mixed-effects model (Statistical Restoration of Fragmented Time course [SReFT]) was applied to datasets of patients provided by the Parkinson's Progression Markers Initiative.

Involvement of multiple cytochrome P450 isoenzymes in drug interactions between ritonavir and direct oral anticoagulants.

Herein, we aimed to determine the significance of drug interactions (DIs) between ritonavir and direct oral anticoagulants (DOACs) and identify the involved cytochrome P450 (CYP) isoenzymes. Using an in vitro cocktail method with human liver microsomes (HLM), we observed that ritonavir strongly inhibited CYPs in the following order: CYP3A, CYP2C8, CYP2D6, CYP2C9, CYP2C19, CYP2B6, and CYP2J2 (IC: 0.023-6.

In vitro-based prediction of human plasma concentrations of food-related compounds.

Efforts have been made to replace animal experiments in safety evaluations, including in vitro-based predictions of human internal exposures, such as predicting peak plasma concentration (Cmax) values for xenobiotics and comparing these values with in vitro-based toxicity endpoints. Herein, the authors predicted the Cmax values of food-related compounds in humans based on existing and novel in vitro techniques. In this study, 20 food-related compounds, which have been previously reported in human pharmacokinetic or toxicokinetic studies, were evaluated.

Significance of Basal Membrane Permeability of Epithelial Cells in Predicting Intestinal Drug Absorption.

Drug absorption from the gastrointestinal tract is often restricted by efflux transport by P-glycoprotein (P-gp) and metabolism by CYP3A4. Both localize in the epithelial cells, and thus, their activities are directly affected by the intracellular drug concentration, which should be regulated by the ratio of permeability between apical (A) and basal (B) membranes. In this study, using Caco-2 cells with forced expression of CYP3A4, we assessed the transcellular permeation of A-to-B and B-to-A directions and the efflux from the preloaded cells to both sides of 12 representative P-gp or CYP3A4 substrate drugs and obtained the parameters for permeabilities, transport, metabolism, and unbound fraction in the enterocytes (f) using simultaneous and dynamic model analysis.

Tumor-associated neutrophils and macrophages exacerbate antidrug IgG-mediated anaphylactic reaction against an immune checkpoint inhibitor.

Background: With the increased use of immune checkpoint inhibitors (ICIs), side effects and toxicity are a great concern. Anaphylaxis has been identified as a potential adverse event induced by ICIs. Anaphylaxis is a life-threatening medical emergency.

Delivery of aPD-L1 antibody to i.p. tumors via direct penetration by i.p. route: Beyond EPR effect.

Chemotherapy for peritoneal dissemination is poorly effective owing to limited drug transfer from the blood to the intraperitoneal (i.p.) compartment after intravenous (i.

Effects of ceramide kinase knockout on lipopolysaccharide-treated sepsis-model mice: Changes in serum cytokine/chemokine levels and increased lethality.

Ceramide, a central molecule of sphingolipid metabolism, is phosphorylated to ceramide-1-phosphate (C1P) by ceramide kinase (CerK). The CerK/C1P pathway regulates many cellular functions, but its roles in immune/inflammation-related (IIR) diseases in vivo are not well known. Sepsis is an acute systemic inflammatory disease accompanied by damage/dysfunction in multiple organs.

Comparison of Predictions by BCS, rDCS and Machine Learning for the Effect of Food on Oral Drug Absorption Based on Features Calculated In silico.

In this study, observed food effects of 473 drugs were categorized into positive, negative, or no effects and compared with the predictions made by machine learning (ML), the Biopharmaceutics Classification System (BCS) and refined Developability Classification System (rDCS). All methods used primarily in silico estimates for prediction, and for ML, four algorithms were evaluated using nested cross-validation to select important information from 371 features calculated based on the chemical structure. Approximately 18 features, including estimated solubility in biorelevant media, were selected as important, and the random forest classifier was the best among four algorithms with 36.

Classification of drugs for evaluating drug interaction in drug development and clinical management.

During new drug development, clinical drug interaction studies are carried out in accordance with the mechanism of potential drug interactions evaluated by in vitro studies. The obtained information should be provided efficiently to medical experts through package inserts and various information materials after the drug's launch. A recently updated Japanese guideline presents general procedures that are considered scientifically valid at the present moment.

Age-Related Change in Hepatic Clearance Inferred from Multiple Population Pharmacokinetic Studies: Comparison with Renal Clearance and Their Associations with Organ Weight and Blood Flow.

Objective: This study aimed to examine the magnitude of age-related change in hepatic clearance by integrating the data of multiple drugs and to compare this with renal clearance, considering associations with age-related changes in organ weight and blood flow.

Methods: The results of multiple population pharmacokinetic analyses that detected age-related clearance changes in hepatically eliminated drugs were collected. The relationship between hepatic clearance of the unbound drug and age was then analyzed using the nonlinear least-squares method, adjusting for interdrug differences.

Effects on Metabolism in Astrocytes Caused by cGAMP, Which Imitates the Initial Stage of Brain Metastasis.

The second messenger 2'3'-cyclic-GMP-AMP (cGAMP) is thought to be transmitted from brain carcinomas to astrocytes via gap junctions, which functions to promote metastasis in the brain parenchyma. In the current study, we established a method to introduce cGAMP into astrocytes, which simulates the state of astrocytes that have been invaded by cGAMP around tumors. Astrocytes incorporating cGAMP were analyzed by metabolomics, which demonstrated that cGAMP increased glutamate production and astrocyte secretion.

Metabolome Shift in Both Metastatic Breast Cancer Cells and Astrocytes Which May Contribute to the Tumor Microenvironment.

The role of astrocytes in the periphery of metastatic brain tumors is unclear. Since astrocytes regulate central nervous metabolism, we hypothesized that changes in astrocytes induced by contact with cancer cells would appear in the metabolome of both cells and contribute to malignant transformation. Coculture of astrocytes with breast cancer cell supernatants altered glutamate (Glu)-centered arginine-proline metabolism.

Investigation of energy metabolic dynamism in hyperthermia-resistant ovarian and uterine cancer cells under heat stress.

Despite progress in the use of hyperthermia in clinical practice, the thermosensitivity of cancer cells is poorly understood. In a previous study, we found that sensitivity to hyperthermia varied between ovarian and uterine cancer cell lines. Upon hyperthermia, glycolytic enzymes decreased in hyperthermia-resistant SKOV3 cells.

A New Intestinal Model for Analysis of Drug Absorption and Interactions Considering Physiological Translocation of Contents.

Precise prediction of drug absorption is key to the success of new drug development and efficacious pharmacotherapy. In this study, we developed a new absorption model, the advanced translocation model (ATOM), by extending our previous model, the translocation model. ATOM reproduces the translocation of a substance in the intestinal lumen using a partial differential equation with variable dispersion and convection terms to describe natural flow and micromixing within the intestine under not only fasted but also fed conditions.

Silencing of VEGFR2 by RGD-Modified Lipid Nanoparticles Enhanced the Efficacy of Anti-PD-1 Antibody by Accelerating Vascular Normalization and Infiltration of T Cells in Tumors.

Despite the promising anticancer effects of immune checkpoint inhibitors, their low objective response rate remains to be resolved; thus, combination therapies have been investigated. We investigated the combination of an anti-programmed cell death 1 (aPD-1) monoclonal antibody with the knockdown of vascular endothelial factor receptor 2 (VEGFR2) on tumor endothelial cells to overcome resistance to immune checkpoint inhibitors and improve the objective response rate. The successful delivery of small interfering RNA to tumor endothelial cells was achieved by RGD peptide-modified lipid nanoparticles composed of a novel, pH-sensitive, and biodegradable ssPalmO-Phe.

Scores of Health-Related Quality of Life Questionnaire Worsen Consistently in Patients of COPD: Estimating Disease Progression over 30 Years by SReFT with Individual Data Collected in SUMMIT Trial.

The aim of this study was to elucidate the lifelong disease progression of chronic obstructive pulmonary disease (COPD) with biomarker changes and identify their influencing factors, by utilizing a new analysis method, Statistical Restoration of Fragmented Time-course (SReFT). Individual patient data ( = 1025) participating in the Study to Understand Mortality and MorbidITy (SUMMIT, NCT01313676), which was collected within the observational period of 4 years, were analyzed. The SReFT analysis suggested that scores of St.